In response to the RFA "Innovative Grants on Immune Tolerance," we propose to test the hypothesis that antenatal exposure to inflammation induces innate immune responses via the fetal lungs that will reprogram postnatal airway responsiveness and immune status. The majority of very low birth weight preterm infants are exposed to chronic indolent chorioamnionitis (inflammation) that can alter lung development and result in bronchopulmonary dysplasia. Many near-term and term infants also are exposed to antenatal infection. We have developed chronic chorioamnionitis models in fetal sheep using intraamniotic injections of endotoxin or live Ureaplasma, the organism most frequently associated with preterm delivery. Fetal sheep exposed to endotoxin develop innate immune paralysis of lung and systemic monocytes as well as other indicators of immune modulation. We will cause chronic chorioamnionitis and lung inflammation in fetal sheep using endotoxin or Ureaplasma parvum. We will evaluate monocyte and lymphocyte responses in the fetus at term in groups of animals. We will randomize other groups of animals to spontaneous delivery and sensitization with house dust mite antigen as newborns. We will then evaluate airway reactivity and immune status at 8 wks of age. The evaluations will include characterization and responses to stimulation in vitro of lymphocytes and monocytes from the blood, lung tissue, caudal mediastinal lymph nodes, spleen and thymus. The experiments will directly test the effects of two clinically relevant fetal exposures on postnatal lung sensitization and function. Relevance to public health: Many preterm and term human fetuses are exposed to chorioamnionitis/ inflammation which can cause profound immune modulation in animal models. Preterms have an increased risk of developing asthma/airway reactivity and the incidence of asthma is increasing in children. This research will use clinically relevant prenatal exposures and postnatal sensitization to establish under controlled conditions any link between antenatal inflammation and the hygiene hypothesis. [unreadable] [unreadable] [unreadable]